Uterine lavage for embryo retrieval

ABSTRACT

A device for recovering one or more blastocysts from the uterus of a human includes an outer guide member for insertion into a cervical canal of the human. The outer guide member includes a distal portion with an activatable seal for isolating the uterus from the external environment and defines a lumen having a longitudinal axis. The device also includes an inner catheter located within the lumen and slidable along the longitudinal axis of the lumen relative to the outer guide member. The inner catheter has a distal tip positionable distally of the seal to extend into the uterus and includes a fluid delivery lumen terminating at a distal fluid delivery port for delivering fluid into the uterus. The device defines a distal suction port for aspirating fluid and entrained blastocysts from the uterus. The distal fluid delivery port and the distal suction port are arranged such that, in use, fluid delivered from the distal fluid delivery port travels through the distal suction port to the uterus.

This disclosure is related to U.S. patent application Ser. No.13/335,170, filed Dec. 22, 2011, titled “RECOVERY AND PROCESSING OFHUMAN EMBRYOS FORMED IN VIVO,” U.S. patent application Ser. No.13/924,470, filed Jun. 21, 2013, titled “UTERINE LAVAGE FOR EMBRYORETRIEVAL,” U.S. patent application Ser. No. 13/924,494, filed Jun. 21,2013, titled “UTERINE LAVAGE FOR EMBRYO RETRIEVAL,” U.S. patentapplication Ser. No. 13/924,510, filed Jun. 21, 2013, titled “UTERINELAVAGE FOR EMBRYO RETRIEVAL,” and U.S. patent application Ser. No.13/924,517, filed Jun. 21, 2013, titled “UTERINE EMBRYO RETRIEVAL,”hereby incorporated by reference in their entirety.

TECHNICAL FIELD

This disclosure relates to uterine lavage.

BACKGROUND

Uterine lavage for recovery and re-implantation of human embryos fromhuman subjects has been performed for the past three decades. Inparticular, in-vivo fertilized embryos have been recovered from fertilewomen and transferred to infertile recipient women, producingdonor-to-recipient transplanted human pregnancies. The first reportedprocedure was performed by a University of Los Angeles team in 1983 andproduced a live birth in 1984.

SUMMARY

In general, in an aspect, at a time when a woman's uterus contains invivo fertilized preimplantation blastocysts, a seal is provided, betweenthe uterus and the external environment, against flow of fluid from theuterus to the external environment. While the seal is provided, fluid isdelivered past the seal and into the uterus. The delivered fluid iswithdrawn, with the blastocysts, past the seal and from the uterus tothe external environment.

Implementations may include one or more of the following features. Therecovered in vivo pre-implantation blastocysts are recovered for geneticdiagnosis or genetic therapy or sex determination or any combination oftwo or more of them. One or more of the blastocysts are returned to theuterus of the woman. The one or more blastocysts are returned to theuterus of the woman without having frozen the blastocysts. Theblastocysts resulted from artificial insemination. The blastocystsresulted from causing superovulation in the woman. At least one of thepre-implantation blastocysts is treated. The treating includes genetherapy. The in vivo fertilized preimplantation blastocysts arewithdrawn from the uterus with an efficiency of greater than 50%. The invivo fertilized preimplantation blastocysts are withdrawn from theuterus with an efficiency of greater than 80%. The in vivo fertilizedpreimplantation blastocysts are withdrawn from the uterus with anefficiency of greater than 90%. The in vivo fertilized preimplantationblastocysts are withdrawn from the uterus with an efficiency of greaterthan 95%. The embryos are frozen. The delivering or withdrawing or bothof the fluid is pulsatile. The fluid is withdrawn while the seal isbeing provided. The seal enables essentially all of the fluid to bewithdrawn. The withdrawing of fluid includes aspirating the fluid fromthe uterus. Both the delivering and the withdrawing are pulsatile andthe pulses of the delivering of the fluid and of the withdrawing of thefluid are coordinated.

In a general aspect, a device for recovering one or more blastocystsfrom the uterus of a human includes an outer guide member for insertioninto a cervical canal of the human. The outer guide member includes adistal portion with an activatable seal for isolating the uterus fromthe external environment, and the outer guide member defines a lumenhaving a longitudinal axis. The device also includes an inner catheterlocated within the lumen and slidable along the longitudinal axis of thelumen relative to the outer guide member. The catheter has a distal tippositionable distally of the seal to extend into the uterus. The innercatheter includes a fluid delivery lumen terminating at a distal fluiddelivery port for delivering fluid into the uterus. The device defines adistal suction port for aspirating fluid and entrained blastocysts fromthe uterus. The distal fluid delivery port and the distal suction portare arranged such that in use fluid delivered from the distal fluiddelivery port travels through the distal suction port to the uterus.

Implementations may include one or more of the following features. Forexample, the inner catheter may include a tubular member that surroundsthe fluid delivery lumen. The tubular member may define the first distalsuction port proximally of the distal fluid delivery port. The innercatheter may include an atraumatic tip positioned distally of the fluiddelivery port. The distal fluid delivery port may be non-circular inshape to provide directional control of fluid spray. The activatableseal may be a balloon collar. The activatable seal may be an expandablefoam.

In another general aspect, a system for recovering one or moreblastocysts from the uterus of a human includes a device and acontroller programmed to cyclically deliver lavage liquid to the uterusvia the fluid delivery lumen and apply vacuum to the device from avacuum source remote from the device. The device includes an outer guidemember for insertion into a cervical canal of the human. The outer guidemember includes a distal portion with an activatable seal for isolatingthe uterus from the external environment. The outer guide member definesa lumen having a longitudinal axis. The device also includes an innercatheter located within the lumen and slidable along the longitudinalaxis of the lumen relative to the outer guide member. The catheter has adistal tip positionable distally of the seal to extend into the uterus.The inner catheter includes a fluid delivery lumen terminating at adistal fluid delivery port for delivering fluid into the uterus. Thedevice defines a distal suction port for aspirating fluid and entrainedblastocysts from the uterus. The distal fluid delivery port and thedistal suction port are arranged such that in use fluid delivered fromthe distal fluid delivery port travels through the distal suction portto the uterus.

Implementations may include one or more of the following features. Forexample, the controller may include a pump for delivering the lavageliquid and a pump for applying the vacuum. The controller may includeelectro-mechanical means for controlling the delivery of lavage fluidand the application of vacuum. The controller may be programmed tocyclically deliver varying amount of lavage liquid. The system mayfurther include a lavage fluid bag for supplying the lavage liquid. Thesystem may further include an embryo recovery trap for receiving theaspirated fluid and entrained blastocysts.

In another general aspect, a process for recovering one or moreblastocysts from the uterus of a human includes placing a devicetrans-vaginally into the cervical canal. The device includes an outerguide member and an inner catheter located within the outer guidemember. The outer guide member includes a seal for isolating the uterusfrom the external environment. The process also includes advancing theinner catheter relative to the outer guide member positioning a distalregion of the inner catheter within the uterus, delivering fluid throughthe inner catheter to the uterus, and applying a vacuum to the uterus toaspirate fluid and entrained blastocysts from the uterus. A distal fluiddelivery port and a distal suction port are arranged such that in usefluid delivered from the distal fluid delivery port travels through thedistal suction port to the uterus.

Implementations may include one or more of the following features. Forexample, placing the device may include locating the seal in thecervical canal. Locating the seal may include locating the seal betweenthe internal cervical os and the external cervical os such that the sealdoes not extend into the vagina or the uterus.

In another general aspect, a process for recovering one or moreblastocysts from the uterus of a human includes placing a devicetrans-vaginally into the cervical canal and cyclically delivering fluidthrough the device to the uterus and applying a vacuum to the uterus toaspirate fluid and entrained blastocysts from the uterus withoutintroducing air into the uterus. A distal fluid delivery port and adistal suction port are arranged such that in use fluid delivered fromthe distal fluid delivery port travels through the distal suction portto the uterus.

Implementations may include one or more of the following features. Forexample, cyclically delivering fluid may include increasing the amountof fluid delivered between cycles.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment and a cervical stop adjustablymounted on the outer guide member relative to the seal for positioningagainst the external cervical os. The outer guide member defines a lumenhaving a longitudinal axis. The device also includes an inner catheterlocated within the lumen and slidable along the longitudinal axis of thelumen relative to the outer guide member. The catheter has a distal tippositionable distally of the seal to extend into the uterus. The innercatheter includes a fluid delivery lumen terminating at a distal fluiddelivery port for delivering fluid into the uterus. The device defines adistal suction port for aspirating fluid and entrained blastocysts fromthe uterus.

Implementations may include one or more of the following features. Forexample, the device may include markings for setting a distance betweenthe seal and the cervical stop.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment and a cervical stop for positioningagainst the external cervical os. The seal has a length in the range ofabout 3 to 8 mm, and the outer guide member defines a lumen having alongitudinal axis. The device also includes an inner catheter locatedwithin the lumen and slidable along the longitudinal axis of the lumenrelative to the outer guide member. The catheter has a distal tippositionable distally of the seal to extend into the uterus. The innercatheter includes a fluid delivery lumen terminating at a distal fluiddelivery port for delivering fluid into the uterus. The device defines adistal suction port for aspirating fluid and entrained blastocysts fromthe uterus.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment. The outer guide member defines alumen having a longitudinal axis. The device also includes an innercatheter located within the lumen and slidable along the longitudinalaxis of the lumen relative to the outer guide member. The catheter has adistal tip positionable distally of the seal to extend into the uterus.The inner catheter includes a fluid delivery lumen terminating at adistal fluid delivery port for delivering fluid into the uterus. Thedevice defines a distal suction port for aspirating fluid and entrainedblastocysts from the uterus. The device includes indicia located on thedevice to be external of the human during use, the indicia providing anindication of the position of the device.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment. The outer guide member defines alumen having a longitudinal axis. The device also includes an innercatheter located within the lumen and slidable along the longitudinalaxis of the lumen relative to the outer guide member. The catheter has adistal tip positionable distally of the seal to extend into the uterus.The inner catheter includes a fluid delivery lumen terminating at adistal fluid delivery port for delivering fluid into the uterus. Thedevice defines a distal suction port for aspirating fluid and entrainedblastocysts from the uterus. The outer guide member and the innercatheter are integrated in the device such that an operator cannotremove the inner catheter from the outer guide member without damagingthe device.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment. The outer guide member defines alumen having a longitudinal axis. The device also includes an innercatheter located within the lumen and slidable along the longitudinalaxis of the lumen relative to the outer guide member. The catheter has adistal tip positionable distally of the seal to extend into the uterus.The inner catheter includes a fluid delivery lumen terminating at adistal fluid delivery port for delivering fluid into the uterus. Thedevice defines a distal suction port for aspirating fluid and entrainedblastocysts from the uterus. The outer guide member and the innercatheter are integrated in the device with the inner catheter having afixed maximum excursion in proximal and distal directions within theouter guide member.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment. The seal has a length in the rangeof about 3 to 8 mm, and the outer guide member defines a lumen having alongitudinal axis. The device also includes an inner catheter locatedwithin the lumen and slidable along the longitudinal axis of the lumenrelative to the outer guide member. The catheter has a distal tippositionable distally of the seal to extend into the uterus. The innercatheter includes a fluid delivery lumen terminating at a distal fluiddelivery port for delivering fluid into the uterus. The device defines adistal suction port for aspirating fluid and entrained blastocysts fromthe uterus. The device does not include an element for expanding theuterus.

In another general aspect, a device for recovering one or moreblastocysts from the uterus of a human includes an outer guide memberfor insertion into a cervical canal of the human. The outer guide memberincludes a distal portion with an activatable seal for isolating theuterus from the external environment. The outer guide member defines alumen having a longitudinal axis. The outer guide member is configuredto be manipulatable by the operator to form a curvature along thelongitudinal axis. The device also includes an inner catheter locatedwithin the lumen and slidable along the longitudinal axis of the lumenrelative to the outer guide member. The catheter has a distal tippositionable distally of the seal to extend into the uterus. The innercatheter includes a fluid delivery lumen terminating at a distal fluiddelivery port for delivering fluid into the uterus. The device defines adistal suction port for aspirating fluid and entrained blastocysts fromthe uterus.

In another general aspect, a system for recovering one or moreblastocysts from the uterus of a human includes a device and acontroller programmed to cyclically deliver lavage liquid to the uterusvia the fluid delivery lumen and apply vacuum to the device from avacuum source remote from the device. The device includes an outer guidemember for insertion into a cervical canal of the human. The outer guidemember includes a distal portion with an activatable seal for isolatingthe uterus from the external environment. The outer guide member definesa lumen having a longitudinal axis. The device also includes an innercatheter located within the lumen and slidable along the longitudinalaxis of the lumen relative to the outer guide member. The catheter has adistal tip positionable distally of the seal to extend into the uterus.The inner catheter includes a fluid delivery lumen terminating at adistal fluid delivery port for delivering fluid into the uterus. Thedevice defines a distal suction port for aspirating fluid and entrainedblastocysts from the uterus.

Implementations may include one or more of the following features. Forexample, the controller may include a pump for delivering the lavageliquid and a pump for applying the vacuum.

In another general aspect, a process for recovering one or moreblastocysts from the uterus of a human includes placing a devicetrans-vaginally into the cervical canal. The device includes an outerguide member and an inner catheter located within the outer guidemember. The outer guide member includes a seal for isolating the uterusfrom the external environment. The process also includes advancing theinner catheter relative to the outer guide member positioning a distalregion of the inner catheter within the uterus, delivering fluid throughthe inner catheter to the uterus, and applying a vacuum to the uterus toaspirate fluid and entrained blastocysts from the uterus.

Implementations may include one or more of the following features. Forexample, placing the device may include locating the seal in thecervical canal. Locating the seal may include locating the seal betweenthe internal cervical os and the external cervical os such that the sealdoes not extend into the vagina or the uterus.

In another general aspect, a process for recovering one or moreblastocysts from the uterus of a human includes placing a devicetrans-vaginally into the cervical canal and cyclically delivering fluidthrough the device to the uterus and applying a vacuum to the uterus toaspirate fluid and entrained blastocysts from the uterus withoutintroducing air into the uterus.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a side view of a lavage device within a female reproductivetract.

FIG. 2 is a side view of the lavage device.

FIGS. 3 a and 3 b are cross-sectional views of portions of the lavagedevice.

FIG. 4 is a close-up perspective view of a distal portion of the lavagedevice.

FIG. 5 is a side cross-sectional view of a handle portion of the lavagedevice.

FIGS. 6 and 7 are side and top views of the lavage device in a retractedposition.

FIG. 8 is a side view of the lavage device in an extended position.

FIG. 9 a is a close-up perspective view of a distal portion of thelavage device.

FIG. 9 b is an exploded view a distal portion of the lavage device.

FIG. 10 is a side view of the lavage device.

FIG. 11 is a front view of a cervical stop of the lavage device.

FIGS. 12-14 are partially cut side views of the lavage device.

FIG. 15 illustrates the lavage device connected to a control cart.

FIG. 16 is an enlarged view of the control cart.

FIG. 17 is a view of a controller interface portion of the control cart.

FIG. 18 is a flow chart illustrating an example process that uses alavage system.

FIGS. 19-29 illustrate a lavage process using the lavage device.

FIG. 30 is a close-up partial view of the control cart of FIG. 15.

FIG. 31 illustrates a step of a lavage procedure.

FIGS. 32-35 illustrate aspects of business models.

FIG. 36 illustrates a procedure performed on a blastocyst.

FIG. 37 illustrates a genetic diagnosis.

FIG. 38 is a side view of an alternative implementation of the lavagedevice within a female reproductive tract.

FIG. 39 is a side view of another alternative implementation of thelavage device.

FIGS. 40 and 41 illustrate an alternative lavage process using thelavage device of FIG. 39.

FIGS. 42 and 43 are side and close-up perspective views of anotheralternative implementation of the lavage device.

FIGS. 44 and 45 illustrate another alternative lavage process using thelavage device of FIG. 42.

FIG. 46 is a side view of a uterine embryo retrieval device.

FIG. 47 illustrates another alternative lavage process using the deviceof FIG. 46.

FIGS. 48 and 49 are side views of another alternative implementation ofthe lavage device.

FIGS. 50 and 51 illustrate another alternative lavage process using thelavage device of FIGS. 48 and 49.

FIG. 52 is a side view of another alternative implementation of thelavage device.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Uterine lavage is performed to withdraw in vivo fertilizedpreimplantation embryos from a woman. The preimplantation embryos areproduced, for example, by superovulation and artificial insemination.Referring to FIG. 1, to perform the uterine lavage, a lavage device 10is inserted into the uterine cavity 12 via the cervical canal 14 and thevagina 16. The uterine cavity 12 is sealed from the external environmentby an activatable seal, for example, an inflatable balloon collar 18 ofthe lavage device 10, and lavage is performed by introducing fluid intothe uterine cavity 12 and withdrawing fluid and entrainedpreimplantation embryos, i.e., blastocysts 20, from the uterine cavity12.

Referring to FIG. 2, a uterine lavage system 22 includes the lavagedevice 10, an inflow section 24, and an outflow section 26. The inflowsection 24 includes a fluid supply line 28 attached to a fluid bag 30,and the outflow section 26 includes a suction recovery line 32 attachedto an embryo recovery trap 34, which is attached to a suction line 36.The lavage device 10 includes an outer, formable guide member 38 and aninner catheter 40 slidably received within the outer guide member 38.

The inner catheter 40 includes a manifold 42 to which the fluid supplyline 28 and the suction recovery line 32 are attached. The manifold 42has a control knob 43 for manipulating the inner catheter 40, andextending distally from the manifold 42, the inner catheter 40 includesa stabilizing bar 44, a supply/suction line 46, and an atraumatic tip48. The outer guide member 38 includes a handle 50, a guide arm 52, acervical stop 54, and a seal, for example, the balloon collar 18. Theballoon collar 18 is inflated using air or liquid delivered by a supplysyringe 56 through a supply line 58 attached to the handle 50. Fluidflow through supply line 58 is controlled by a stopcock 60.

Referring to FIGS. 3A and 3B, the supply/suction line 46 of the innercatheter 40 is a coaxial tube including an outer tubular member 62 andan inner tubular member 64. Defined between the tubular members 62, 64is an outflow lumen 66 for aspiration of fluid and entrained blastocystsfrom the uterine cavity, and the inner tubular member 64 defines aninflow lumen 68 for delivery of lavage fluid to the uterine cavity. Theouter guide member 38 includes a formable tube 70 located within a lumen72 of the guide arm 52. The formable tube 70 surrounds a support member74, which defines a lumen 76 connected to the balloon inflation supplyline 58. FIG. 4 shows the termination of the supply lumen 76 at theballoon collar 18. Support member 74 defines a lumen 78 (FIG. 3A) thatreceives the supply/suction line 46 of the inner catheter 40.

Referring to FIG. 5, the handle 50 defines a slot 80 that receives thestabilizing bar 44. When the inner catheter 40 slides axially relativeto the outer guide member 38, the stabilizing bar 44 slides along theslot 80. The stabilizing bar 44 helps support the manifold 42. Asillustrated in FIG. 6, the stabilizing bar 44 includes indicia 82 thatindicate the extent of insertion of the inner catheter 40 relative tothe outer guide member 38. The inner catheter 40 can be moved axiallybetween the retracted position of FIGS. 6 and 7, and the extendedposition of FIG. 8. The stabilizing bar 44 terminates in a head 81 andthe handle 50 includes a stop 83 which prevents the head 81 from exitingfrom the slot 80 such that the inner catheter 40 and the outer guidemember 38 are permanently joined to form a single, integrated device,i.e., the supply/suction line 46 cannot be completely removed from theouter guide member 38 by the operator.

Referring again to FIG. 5, the inner tubular member 64 of supply/suctionline 62 is supported by a resin block 84 in manifold 42.

Referring to FIGS. 9A, 9B and 10, the inner tubular member 64 of thesupply/suction line 46 defines a fluid supply line port 86, for example,two diametrically opposed ports, through which fluid is delivered to theuterine cavity. The ports can be non-circular in shape to providedirectional control of fluid spray. For example, the proximal side ofthe port can be perpendicular to the longitudinal axis of the innertubular member 64 and the distal side of the port can diverge from theaxis at an obtuse angle. The outer tubular member 62 of thesupply/suction line 46 terminates proximal of port 86 and the atraumatictip 48 defines fluid suction line ports 88 that are in fluidcommunication with outflow lumen 66 through which fluid and entrainedblastocysts 20 are recovered from the uterine cavity. The position ofthe suction line ports 88 about fluid supply line port 86 avoidsplugging of the suction recovery line port 88 with mucous.

As shown in FIG. 4, the lavage device 10 includes a priming cap 350 thatis used to cover the ports 86 and 88 providing a seal to allow primingof the device prior to use.

The position of the cervical stop 54 is adjustable relative to theballoon collar 18 along a cervical stop scale 94 (FIG. 10) on the guidearm 52. The position of the cervical stop 54 defines a dimensioncorresponding to a distance from an opening of the cervix at the vagina(the external cervical os) and an opening of the cervix at the uterus(the internal cervical os). The cervical stop 54 can be clamped in a setposition along the guide arm 52. Referring to FIG. 11, the cervical stop54 includes a locking ring 96 and flange adjustment grips 98. In itsrest state, the locking ring 96 is not circular in shape and has aninner dimension smaller than the outer diameter of the guide arm 52 tolock the cervical stop 54 in position. By squeezing in on the flangeadjustment grips 98, the operator can deform the shape of the lockingring 96 to a more circular shape that can slide along the guide arm 52to adjust the position of the cervical stop 54. Upon release of thesqueezing force, the locking ring 96 returns toward it rest state,locking the cervical stop 54 in place. The cervical stop 54 is shaped tohave a visual port 99 that allows the operator to see the cervix andalign the atraumatic tip 48 during insertion of the uterine device 10.The cervical stop scale 94 is etched into the outside of the catheterguide arm 52 and marks the position of the cervical stop when it iscustom-adjusted to each patient prior to insertion.

Referring to FIGS. 12-14, the formable tube 70 can be bent into adesired position by the operator to allow the atraumatic tip 48 and thesupply/suction line 46 of the lavage device 10 to travel through thecervical canal and into the cervix with minimal discomfort to thepatient. The angle can be preset from about 0 to 60 degrees and iscustomized to individual women in order to accommodate the differentanatomical variations of the uterine flexion. FIG. 13 shows the formabletube 70 modified to 30 degrees up, and FIG. 14 shows the formable tube70 modified to 30 degrees down. The formable tube 70 is made, forexample, from Stainless Steel, is coated with polyamide, and includescut-outs 75.

The outer guide member 38 has an outer diameter in the range of, forexample, 6-7 mm, and is made from, for example heat shrink polyolefin orp-bax elastomeric over layer. Inner catheter 40 has an outer diameter inthe range of, for example, 3-6 mm, and for example, 3.05 mm, and ismade, for example, from stainless steel. Cervical stop 54 has a diameterof, for example, 19.05 mm and is made, for example, from polyamide. Thelavage device 10 is sized for use without anesthesia.

Referring to FIGS. 15 and 16, the uterine lavage system 22 includes acontrol cart 100 used to connect the lavage device 10 to the lavagefluid bag 30 and the embryo recovery trap or collection bottle 34, andto control the inflow of fluid to the uterine cavity and the removal offluid and entrained blastocysts from the uterine cavity. The lavagefluid bag 30 is supported by the cart 100, and the supply line 28 isrouted from the fluid bag 30 through a peristaltic fluid pump 102 to thelavage device 10. Blastocysts 20 are recovered through the lavage device10 and travel to the collection bottle 34 via the suction recoverychannel 32. The collection bottle 34 is connected to a vacuum supplyconnector 104 via the suction line 36 through which suction is appliedto suction recovery channel 32. The application and level of suction iscontrolled by a pinch valve 108. The introduction of fluid is controlledby the pump 102. The lavage fluid is drawn from the bag 30, pumpedthrough the supply line 28, and pulsed in and out of the uterus throughthe atraumatic tip 48. The pump 102 supplies uterine lavage fluid in apulse rhythm with a vacuum element that alternates suction and pulsescadenced the opposite to the fluid delivery at a preset frequency of,for example, 0.5 to 4.0 seconds with less fluid being aspirated thandelivered to ensure that air is not introduced into the uterine cavity.

The control system manages pulse and flow via electro-mechanical means(software instructs the control system in use of vacuum and pulse offluid delivery). The control system is reprogrammable such that softwarecan be loaded that alters the pulse frequency, the pressure of fluidsupply, the frequency of vacuum pressure, amount of vacuum supplied, andthe frequency and duration of pause steps between pressure and vacuumsupply.

Referring to FIG. 17, a user interface 130 for controlling the system 22includes a power button 132, a prime button 134, a treat button 136, apause button 138, and a finish button 140. The power on/off button turnson an electrical power supply to the control system. The Prime buttonstarts the fluid supply pump and keeps the pump running for the durationof the time that the button is depressed. The Treat Button starts thelavage cycle invoking the software to execute a pattern ofpulse-pause-vacuum-pause until the fluid supply is utilized fully. TheFinish button stops the lavage cycle. Faults in the set-up of the lavagedevice or with the software during the lavage cycle are indicated on aLED screen 142 and the control system automatically pauses the lavagecycle until the problem is resolved. The user interface 130 produces aseries of electronic beeps indicating when a portion of the lavage cycleis completed. Beeps occur after each treat cycle and after the finishcycle is completed.

The IV bag 30 is a standard format, latex free, PVP free, DEHP free IVbag that can hold requisite lavage fluid solutions. The IV bag holds nomore than the total amount of lavage fluid to be used in the lavagecycle. The IV bag is attached to the lavage system via a standard spikeand tube format. The IV bag is translucent such that the operator canmonitor fluid movement from the IV bag though the tubing and thecatheter.

Referring to FIG. 18, the lavage system 22 is used in one or more stepsof a procedure that includes superovulation 200, artificial insemination202, preparation and set up 204, uterine lavage cycle 206, shipment anddelivery of blastocysts recovered during the lavage process 208,shutdown cycle 222, embryo biopsy 210, molecular diagnosis 212,intervention 214, cryopreservation 216, embryo replacement 218, andending in the birth 220 of a healthy baby.

Preparatory to lavage, prior to superovulation and insemination, apractice lavage can be performed (approximately one or two months)before the live procedure is scheduled. In the practice lavage,measurements are taken (with the assistance of imaging technologies) andthe lavage device 10 is custom fit to enable the anatomy of each patientto be accommodated. Precise imaging of each woman's anatomy utilizesimaging devices, for example, two-dimensional or three-dimensionalultrasound, magnetic resonance imaging, or other imaging technology. Theoperator determines the optimal position for cervical stop 54 andrecords the reading on the scale 94, the optimal insertion ofstabilizing bar 44 and records the reading on the indicia 82, the anglethe lavage device is to be set at by modification of the formable tube70, and the amount of inflation of the balloon collar 18 to accommodatethe degree of cervical dilation of the patient.

Superovulation is caused in a woman to form multiple corpora lutea thatundergo apoptosis and cannot support development of a viable implantedpregnancy following shutdown 222. In-vivo fertilization of multipleoocytes by artificial insemination and/or natural insemination isfollowed by maturation of the fertilized oocytes to form multiple maturepreimplantation embryos that present to the uterine cavity asblastocysts.

To cause superovulation, FSH is delivered to the woman's body. The FSHcan be delivered by self-injection. The dosage of FSH is appropriate forinduction of superovulation, in vivo fertilization, and embryonicmaturation. The FSH is, for example, self-injected daily for 5 to 15days in the range of 5 to 600 mIU per day. The FSH includes at least oneof injectable menotropins containing both FSH and LH; purified FSH givenas urofollitropins; recombinant pure FSH; or single doses of long actingpure FSH (recombinant depot FSH), including administering GnRHantagonists to quiet the ovaries while causing superovulation. The GnRHantagonists include receptor blocker peptides. The GnRH antagonistsinclude at least one of Cetrotide 0.25 to 3.0 mg, Ganirelix, Abarelix,Cetrorelix, or Degarelix in which causing superovulation includesadministering GnRH including administering a single dose of hCG agonistsubcutaneously or snuffed to trigger the superovulation. The GnRHincludes at least one of Leuprorelin, Leuprolide acetate, Nafarelin, orNaferelin acetate snuff 117 including administering LH or hCG withoutGnRH agonist including administering LH or hCG or in combination withGnRH agonist in which impaired (apoptosis) corpus luteum estradiol andprogesterone production is supplemented to maintain embryonic viabilityand maturation by including administrating progesterone and estradioluntil recovery of the blastocysts. The progesterone includes at leastone of vaginal progesterone, or oral progesterone and the estradiolincludes at least one of oral or transdermal estradiol. The progesteroneincludes Crinone® 1 application per day or Prometrium® 200 mg 3applications per day or Prometrium® 200 mg 3 oral capsules per day, andthe estradiol includes transdermal estradiol patches 400 ug per day ororal estradiol 0.5 to 5.0 mg per day in which blastocyst implantation isprevented by discontinuing administration of estradiol and progesteronestarting on the day of blastocysts recovery on the day of lavage.Desynchronization includes administering progesterone receptorantagonist. The administering includes a single dose of progesteronereceptor antagonist (Mifepristone 600 mg) injected into the uterinecavity with a second dose (Mifepristone 600 mg) mg given by mouth oneday prior to expected menses. Desynchronization includes administeringGnRH antagonist on the day on which the blastocysts are recovered toinduce further corpus luteum apoptosis, suppress luteal phaseprogesterone, and further decrease risk of a retained (on account ofblastocysts missed by the intrauterine lavage) pregnancy. The GnRhantagonist includes Cetrotide 0.25 to 3.0 mg.

Uterine lavage is typically performed between 4 and 8 days after the LHdose or LH surrogate trigger that released in vivo the multiple oocytesresulting from the superovulation. Referring to FIG. 19, at the optimaltime (most likely day 6), the blastocysts 20 are located between theanterior and posterior uterine walls at approximately the geometriccenter of the uterine cavity 12. This location is in close proximity tothe ultimate site of implantation, which is believed would take placewithin one day or less after the procedure if the blastocysts 20 werenot recovered.

In preparation for the live lavage, the disposable and reusable elementsof the instrument are selected based on the prior measurements and studyof the woman's anatomy, and assembled and attached to the pulsing andsuction elements, ready for the procedure. The operator sets thecervical stop 54 at the position determined on the cannula that ensuresthe balloon collar 18 is positioned along the internal cervical os 230.The cervical stop 54 is set relative to the measurement markings on thecervical stop scale 94 that defines the distance from the balloon collar18, which has been premeasured by the device operator, and is clamped tothe catheter guide arm 52.

The operator then shapes the catheter guide arm 52 as predetermined bythe operator such that when the lavage device 10 is placed into theuterus the atraumatic tip 48 is positioned for extension along themidline of the uterus. The catheter guide arm 52 is flexible and willhold its shape via internal formable tube 70, and is bent into positionto accommodate the position of the uterus relative to the particularwoman's body (anteverted, retroverted, cast medially or laterally or anycombination therein). The anatomy of the patient in question has beendocumented in prior exams such that the uterus position information canbe used to prepare the lavage device for the uterine lavage cycle.

Temperature preparations are completed such that prior to the lavagecycle the fluid bag 30 with lavage fluid is pre-heated to 37 degreesCelsius by placing the fluid bag on a heating plate for a period of 30minutes. The embryo recovery trap 34 is preheated for 30 minutes byplacing a heating wrap around the container. This step ensures that theblastocysts 20 will be sustained at 37 C for the time period just afterremoval from the uterus through the arrival at an embryology laboratory.

Prior to the lavage cycle, the operator primes the lavage device 10 withlavage fluid as follows: turns on the lavage device controller bypressing the ‘Power’ button 132 (FIG. 17) located on the control panelof the controller; presses and holds the ‘Prime’ button 134 on thecontrol panel of the controller; and holds the ‘Prime’ button 134 downuntil the lavage fluid is pumped through the fluid supply line 28 andthe suction recovery channel 32 of the lavage device 10 and depositsfluid into the embryo recovery trap 34. After priming is complete, theoperator removes the priming cap 350 and the device is ready forinsertion into the patient.

The lavage procedure is conducted as follows:

i) Intracervical Insertion:

The procedure begins with insertion of the lavage device 10 into theuterine cavity 12 via the cervical canal 14 through the vagina 16. Thelavage device 10 is inserted until the cervical stop 54 rests againstthe external surface of the cervix 14 (external cervical os 232)creating a fluid-tight seal, protecting the vagina 16 (FIG. 19). Thedeflated balloon collar 18 lies at the end of the cervical canal 14 atthe entrance to the uterus (internal cervical os 230).

ii) Insufflation:

Creation of Cervical Seal: The cervical seal balloon collar 18 is theninflated (FIG. 1) to provide a watertight seal at the internal cervicalos 230 to prevent the loss of lavage fluid around the lavage device 10.This is done by depressing the syringe 56 until 1.5 cc to 3 cc of fluid,air or liquid, is injected into the balloon collar 18, or untilsufficient resistance to balloon inflation is felt by the operator. Thestopcock 60 is then closed to ensure the balloon collar 18 remainsinflated throughout the duration of the procedure. In some cases,especially for nulliparous women, balloon inflation may not be requiredto gain a seal at the internal cervical os 230.

iii) Positioning of Catheter Tip in Center of Uterus:

The final step prior to performing the lavage cycle is positioning ofthe atraumatic tip 48 as close to the center of the uterine cavity 12 aspossible. The operator utilizes predetermined dimension information thatspecifies the length of the uterus from the external cervical os 232 tothe fundus 234 to set the position of the catheter tip 48 as follows:hold the lavage device using the handle 50; extend the atraumatic tip 48into the uterine cavity 12 (FIG. 20) by pushing the manifold 42 slowlyforward until the tip 48 touches the fundus 234. The operator knows whenthe catheter tip touches the fundus when resistance is felt as the tip48 is being extended into the uterus while depressing the manifold 42.The operator retracts the atraumatic tip 48 2.0 cm back from the fundus234 (FIG. 21). The operator may opt to utilize uterine ultrasound eitherabdominally or vaginally to verify correct placement of the atraumatictip 48. The lavage device 10 including its fluid supply and vacuum linesis now in its semi-extended position, approximating the center of theuterus where blastocysts 20 are located. The operator may extend thedevice position as the lavage cycle progresses as needed or desired foruse.

Alternatively, the position of the atraumatic tip 48 is determined bymonitoring the indicia 82 on the stabilizing bar 44.

iv) Uterine Lavage & Embryo Recovery:

The lavage cycle (FIGS. 22-27) is started by depressing the ‘treat’button on the control panel. The first stage of the lavage cycle isbegun by injecting a small amount of fluid 260 (FIG. 22) into theuterine cavity 12 for form a puddle 262 of fluid (FIG. 23) encompassingthe blastocysts 20. All of the fluid present in the uterine cavity 12 isthen suctioned into the catheter (FIG. 24) along with one or moreentrained blastocysts 20. The second stage of the lavage cycle is begunby injecting a larger amount of fluid into the uterus to form a largerpuddle 264 (FIG. 25). All of the fluid present in the uterine cavity 12is then suctioned into the catheter (FIGS. 26 and 27) along with one ormore entrained blastocysts 20.

Lavage fluid is delivered and vacuumed in alternating pulsed cycles ofinject, dwell, and vacuum through the dual lumen atraumatic tip 48.Using the indicia 82 on the stabilizing bar 44, the position of theatraumatic tip 48 can be changed for each cycle. For example, a firstcycle can be with the atraumatic tip 48 at zero extension, and cyclestwo through five can be at increasing extension increments that are aquarter of the distance to the fundus 234, with the amount of fluiddelivered increasing in each subsequent cycle. The dual focused streamsof fluid directed to the uterine cavity wall at a point below theinternal ostia 236, 238 form a functional hydraulic wall through whichthe embryos cannot move retrograde from the middle uterine cavity intothe respective right and left internal tubal ostia 236, 238.

The lavage cycle is repeated and controlled by the lavage devicecontroller. The lavage cycle operates for approximately 3 minutes, oruntil 100% of the lavage fluid (maximum 5 minutes) located in the fluidbag 30 is cycled through the lavage device 10, into the uterus andremoved via the suction recovery channel 32 into the embryo recoverytrap 34. The operator monitors the lavage cycle visually by watchingfluid flow. While the lavage cycle is operating the fluid flow willpulse through the fluid supply line 28 and suction recovery channel 32.The fluid quantity will decrease in the fluid bag 30 and increase in theembryo recovery trap 34. The recovered lavage fluid will appear cloudydue to presence of uterine fluid and endometrial tissue captured fromthe lavage process and recovered from the uterus. The embryos arewithdrawn from the uterus with an efficiency of at least 80%. Theembryos are withdrawn from the uterus with an efficiency of at least90%. The embryos are withdrawn from the uterus with an efficiency of atleast 95%. Desynchronization of the endometrium is caused to reduce thechance that any embryos remaining in the uterus will form a viablepregnancy.

v) Jamming:

(Optional step to address lack of fluid flow in catheter during thelavage cycle): Jamming is the term which describes a lack of fluid flowand can occur due to the buildup of endometrial tissue at the atraumatictip 48. The following steps can be taken in the event of jamming: pressthe Pause button on the lavage device controller control panel, adjustthe position of the catheter tip and restart the lavage cycle, repeat asneeded, when flow is detected in the suction recovery channel allow thelavage cycle to complete.

vi) Completion and Stop of the Lavage Cycle:

The lavage cycle is complete when (1) the fluid bag is empty and (2) thecontroller system has operated for at least one minute after all fluidis visibly removed from the fluid bag, supply line and suction recoverychannel. The lavage procedure automatically ends after a sustainedduration of vacuum only cycle is completed or when the operatordepresses the ‘Finish’ button twice. The operator then turns off thelavage controller by depressing the power button.

vii) Removal of Lavage Device:

The operator removes the lavage device as follows: pull the manifold 42away from the handle 50 to retract the inner catheter 40 into the outerguide member 38 (FIG. 28); deflate the balloon collar 18 by opening thestopcock 60 and retracting the syringe 56 to 0 cc (FIG. 29); the lavagedevice 10 is then slowly removed from the cervix 14.

Referring to FIG. 30, the recovered blastocysts 20 are located in theembryo recovery trap 34, which is also the container used fortransportation of the blastocysts 20 to an embryology laboratory. Theoperator disconnects the embryo recovery trap 34 from the device 10 by‘snapping’ the connections just above the top of the embryo recoverytrap 34. The embryo recovery trap 34 is then placed into a preheatedcontainer 240 (FIG. 31) that secures the embryos for transport, ensuringthat the recovered blastocysts 20 are in an environment in which theywill thrive. Multiple individual sample containers 240 can be placed ina transport carrying case 242 (FIG. 31). Each recovery trap 34 is sealedby a glass stopper 244 and labeled with an ID label 246.

The fluid used in the lavage cycle may be lactated Ringers, HTF (HumanTubal Fluid), modified HTF, or HEPES-buffered media. The operatordetermines appropriate solutions based upon knowledge and preference.The operator receives recommendations as follows for fluid choice: (1)non-heparin based media (2) non CO2 based media that isapproved/generally accepted for use in humans.

The uterine lavage procedure is performed under low flow and vacuumconditions, not to exceed the maximum pressure allowed by the device ofbetween 2 ounces per square inch and 20 pounds of pressure per squareinch and 10-14 Hg of vacuum pressure to maintain the integrity of theblastocysts during fluid delivery and removal. The uterine cavity is notexpanded or pressurized. The lavage device 10 does not include anymembers that act to expand the uterine cavity, as such an expansion canintroduce air into the uterine cavity, which can kill the blastocysts20. The lavage process, as well as its preparatory steps and finishinstructions, are designed to prevent the introduction of air into theuterine cavity to ensure the health and integrity of the recoveredblastocysts.

Shown in FIG. 32 are examples of how the procedures can be delivered andmanaged. A corporate managed regional coordination center 300 (alsosometimes called the host of the network) owns and manages or franchisesthe operation of a number of core laboratories 302 (only one shown)located in high-density population centers across the United States. Thelocation of each of these laboratories 302 is based upon a service area304 that is within a defined surface travel time or distance to thelaboratory 302. For example, a service area can be one served by groundtransportation of a distance of approximately 150 miles radius or lessthan 4 hours transportation time from the laboratory 302, or withreliable delivery by air to the laboratory 302 within a flight time ofless than 4 hours. Examples of suitable cities include New York (2centers), San Francisco, Los Angeles, Boston, Chicago, Philadelphia,Washington D.C., Seattle, Minneapolis, Miami, Atlanta, Denver, Dallas,Phoenix, and Memphis.

In some implementations, each of the core laboratories 302 is imbeddedin an existing embryological molecular genetic service laboratoryalready existing in a major, high profile medical center. Each of thecore laboratories 302 is supported and electronically linked to its ownregional network of subscriber clinics 306. The host 300 of the networkleases or partners with existing core laboratories 302 capable ofproviding embryology, cryogenic, and molecular genetic services (or somepart of them) for embryos acquired in their service areas same day.

The network host's subscriber clinics 306 are points of patient contactand care services. Physicians and support staff working in these localclinics 306 are subscribers to the network host's systems. Among otherthings, to become a subscriber a clinic has to include high securityareas 310 in their clinics and computer linkages 312 that are managed bythe network host 300 and solely devoted to network host operations attheir site. Physicians and support staff working in subscriber clinics306 will have been previously established as practitioners ofreproductive endocrinology, infertility, and genetics.

Patients 314 seeking the network host's services are referred to asubscriber clinic 306 located near their home or business. There need beonly limited disruption of a patient's personal life while she isreceiving services in the system. The ordering of the central host'sembryological services, genetic testing, and obtaining of results is assimple as ordering routine laboratory testing as practiced today.

As seen and experienced by an individual patient 314, the process beginswith the patient 314 entry at a local network subscriber clinic 306,embryo recovery at the clinic, followed by embryo diagnosis, decision,treatment if possible, and replacement of her embryos at the subscriberclinic 306. The steps of counseling, consenting, superovulation,artificial insemination, and lavage take place in subscriber clinics 306under the direction of the clinic physician and staff. Network personnelperform lavage at the subscriber clinic 306, transport the recoveredblastocysts, process the blastocysts at the core laboratory 302, returnthe blastocysts to the subscriber clinic, and transfer the blastocystsback to the women's uterus at the subscriber clinic 306, with follow-upand confirmation of the pregnancy being done in the woman's local healthcare system.

Patient 314 entry begins at the subscriber clinic 306 where she and herpartner have been referred by herself or by a physician in anticipationof her becoming pregnant. After review of the genetic reproductivehistory, a subscriber's reproductive endocrinologist geneticist willmake the decision that the network's procedure is appropriate and willcontact the network's core laboratory 302 through their subscriber link.The patient's data will be entered locally at the subscriber clinic 306along with appropriate demographics, financial, and insurance data. Thenetwork regional coordinating center 300 will review the data entriesand, as appropriate, approve of that patient's entry after review ofhistory and laboratory data.

The network's nurse practitioner staff will see the patient in person atthe subscriber clinic 306, customize and fit the lavage device to thespecific anatomy of that patient using traditional or 3D ultrasoundimaging, and approve her for launch (starting superovulatory drugs) ofher cycle. The network's regional coordinating center 300 will thenauthorize initiation of the drug induced superovulation induction.Subscriber clinic physicians prescribe and administer superovulatorydrugs under protocol, conduct the monitoring, and report the patient'sprogress in real time using online links to the network's regionalcoordinating center 300. Superovulation (actual release of oocytes forfertilization) will be triggered by protocol and managed by subscriberclinic physicians. The woman will then appear in the subscriber clinic306 with her partner, and after documenting security clearance usingelectronic chips and face-iris recognition (in other words, confirmingthat the woman is the person who she purports to be and is the patientto be processed), the subscriber clinic personnel, with approval by thenetwork regional coordinating center 300, will perform intrauterineinsemination of the woman at approximately 36 hours after triggeredsuperovulation. Sperm samples will be prepared in the onsite networksecure laboratory site 310 with identities re-confirmed electronicallyby the patient's and her partner's electronic identification cards thatare programmed, for example, with confirmatory facial recognitions andiris scans.

Uterine lavage will be performed at the subscriber clinic by the networknurse practitioner at between 5 and 7 days after insemination. Therecovery fluid is diluted with embryo protective transport media addedimmediately to the lavage fluid at recovery and is transported in sealedinsulated containers 240 (FIG. 31) that are marked by the electronicidentification chips 246 linked to the women and her partner.

After lavage, the subscriber clinic 306 electronically notifies the corelaboratory 302 by way of the secure computer network link of the statusand location of all blastocysts 20 in process in the network at thattime. At each step in the process after lavage, information recordedelectronically as identity chips attached to each clinical andlaboratory step is scanned and stored in the network system dataprocessing facilities to maintain a history of the steps and the currentlocation of the blastocysts 20. Thus, the exact location of allblastocysts and cells retrieved from all patients is known in real timeas identification chips are passed through scanners from lavage, torecovery in the laboratory, to biopsy, to genetic diagnosis, genetictherapy, or sex determination (or any two or more of those), tofreezing, thawing, and placement back into the patient. The identity ofall patients and their partners is confirmed, for example, byiris/retina scans, electronic face recognition, and identification cardsat each contact. Software is also be used to manage lab reports,clinical data from each patient and her partner, contact information,and billing and insurance arrangements.

Blastocysts 20 are delivered to the core laboratory 302 in the samelavage fluid, diluted in transport media that was used for the lavagerecovery. The containers 34 in their insulated transport blocks 240obtained from the day's procedures are carried in secure carrying cases242 transported by the nurse practitioner. On arrival at the corelaboratory 302 and on delivery to a secure network laboratory space 310(FIG. 54), the lavage containers 34 are matched electronically afterscanning to the identification system and then placed in an individualspace allocated only to those blastocysts. An identification database322 maintained in the corporate regional coordinating center 302contains all instructions on the type of biopsy procedure to beperformed, and the diagnostic tests to be performed on the biopsiedcells relevant to that patient.

After the embryologist manually isolates and confirms identify from scanof the electronic chip 246 attached the transport container 34, each ofthe blastocysts is graded for viability by the embryologist, placed on amicromanipulator in an electronically marked petri dish, and undergoesselective trophectoderm-inner cell mass biopsy. Approximately 10 to 20trophectoderm 334 or inner cell mass cells 336 are obtained andsubmitted to molecular genetic analysis as directed by orders in thepatient's database and dependent upon indications for the specificprocedure.

Referring to FIG. 36, when utilizing a micromanipulation apparatus,individual blastocysts 20 in individual Petri dishes under blastocystculture and heated fluid (typically 37 C) are positioned onto the tip ofa fire-polished pipette 330 and stabilized by application of gentlesuction on the lumen of the pipette. The zone pellucida is openedmechanically with another pipette 332 or with a laser beam to exposeeither the trophectoderm (future placenta—334) or inner cell mass(future fetus—336) of the blastocyst, which are removed via the pipette332. It is likely that with existing or future nano surgical technologyit will be possible to recover from one to many targeted cells 334, 336for molecular genetic diagnosis or sex determination.

The recovered trophectoderm cells 336 or inner cell mass 334 obtainedfrom targeted embryonic regions are placed in blastocyst media in petridishes or small tubes and then undergo molecular genetic diagnosis orsex determination or both. Molecular methods are selected for thecondition being evaluated. Established techniques include one or more of(or combinations of any two or more of: in situ hybridization toevaluate chromosomal structures, polymerase chain reaction directed todetect specific mutations or other defects gene organization, wholegenome hybridization, microarray gene chips, exome sequencing, oranalysis of the entire human genome. A geneticist evaluates themolecular analysis in combination with information about specificclinical factors of the case. A decision is then made that leads to (a)replacing the embryo in the mother, as unaffected by the disease inquestion, (b) recommending an intervention such as gene therapy ortransplantation of donated stem cells, or (c) recommending that theembryo not be replaced and that another embryo which is unaffected bereplaced at a later time.

Referring to FIG. 37, a common example of a molecular diagnosis (Downsyndrome) 340 currently possible from human blastocysts using eithersingle trophectoderm or very early fetal cells is illustrated. Thisfigure depicts an example in which specific areas of chromosomes aretargeted at a molecular level fluorescent in situ hybridization (FISH)342 with fluorochromes, which produce a microscopically visible signalwhen linked. In this example, a diagnosis of Down syndrome isdemonstrated by the presence of three #21 chromosome signals 340. Alsoseen are two X-signals 344 indicating female gender, two (#18)-signals346, and two (#13) signals 348 as would be encountered normally.

A wide variety of analyses can be applied. For example, the molecularanalysis can include one or more of the following: in situ hybridizationto evaluate chromosomal structures, polymerase chain reaction directedto detect specific mutations or other defects gene organization, wholegenome hybridization, microarray gene chips, exome sequencing, oranalysis of the entire human genome as indicated. Tests can be performedin duplicate for confirmation, because 10-20 cells should be adequate.The biopsied blastocysts 20 are frozen or vitrified in liquid nitrogenfor preservation. Within 24 to 48 hours, the results can be placed onthe secure electronic network and reported to the subscribers anddiscussed with the patient and partner.

The status of each embryo and the results of the genetic analysis arereported by secure link in real time to each subscriber clinic 306through its secure computer terminal 312. The subscriber clinic 306 alsocontacts the patient and her partner. The subscriber selects a strategy.Blastocysts 20 identified as suitable for replacement are deliveredcryopreserved to the subscriber's clinic 306 for replacement at a latertime, in days, weeks or months.

At an appointed time, the frozen blastocyst 20 selected for transfer isdelivered to the subscriber's clinic by the nurse practitioner in asecurity-coded container that is matched to the identification of thepatient and her partner using an electronic identification chip.Identities of the patient and her partner are reconfirmed with facialrecognition and iris/retina scans. The blastocysts 20 is thawed in thesubscriber's network protected facility, photographed, loaded into atransfer catheter under the supervision of the nurse practitioner, andthen transferred into the patient by the network nurse practitioner.

Resulting pregnancies are followed by the subscriber clinic and prenatalcare will take place in the clinical infrastructure of the region.

Contractual arrangements between the network system and corelaboratories and subscriber clinics and laboratories include securespace and equipment allocated exclusively to network operations. Theglassware and all laboratory equipment involved with network iscolor-coded and inventoried for no other uses except network patientsand personnel specially employed or contracted by the network. Everystep involved in the flow and management of the blastocysts 20 is markedelectronically and linked to the identity data of the patient and herpartner. Births, perinatal outcomes, and genetic evaluations also takeplace in the local infrastructure and are documented and archived in thenetwork database. Long-term follow-up of the births and progress of thechildren into adulthood is readily achievable using information from thenetwork database with confidentiality limits set within U.S. Governmentstandards.

The information that is derived from containers in which sets ofpre-implantation embryos recovered from respective women are held isreceived electronically. The information uniquely identifies the sets ofembryos and reliably associate them with the respective women. Digitalrecords of the respective sets are persistently maintained that containinformation about the transporting and processing of the embryos. Theinformation is derived from secure encrypted markers associated with thecontainers. Each of the sets of embryos is moved from container tocontainer in the course of transporting and processing. The digitalrecords are maintained by a host on behalf of providers of services withrespect to the sets of embryos. The host provides electronic dataservices to a set of clinics with respect to services provided by theclinics to women related to in vivo pre-implantation embryos recoveredfrom the women. The providing of the data services includes collectingdata that tracks the transporting and processing of the embryos, andproviding access to the clinics of data that reports the tracking.

Referring to FIG. 38, a lavage device 10 a can include a secondarysuction port 88 a provided through lumen 78 (FIG. 3A) near internalcervical os 230. The lavage device 10 a includes a cervical stop in theform of a vacuum cup 54 a. Vacuum applied to the cup 54 a acts to attachand seal the cup 54 a to the external cervical os. The operator can thenpull on the lavage device 10 a to straighten the woman's uterus. Any ofthe described lavage devices described can be used with a cervical stop54 or a vacuum cup 54 a.

Referring to FIGS. 39-41, the outer tubular member 62 a of thesupply/suction line 46 of the inner catheter 40 of a lavage device 10 bcan terminate in a funnel 62 b that flares to a large vacuum opening 62c for collecting lavage fluid and entrained blastocysts. Thesupply/suction line 46 can be steerable by the operator to adjust theposition of the tip 48 within the uterine cavity. By positioning the tip48 at the surface of the wall of the uterus, the lavage device usesmechanical agitation, touching and agitating the surface, to loosenmucus and recover blastocysts in the mucus. The tip 48 and funnel 62 bcan be moved along the wall of the uterus by rotating the lavage device10 or extending and retracting the inner catheter 40.

Referring to FIG. 42-45, a lavage device 10 c includes an inner catheter40 have dual supply lines 46 a, 46 b. Each supply line 46 a, 46 bdefines fluid openings 46 c, for example, four to five openings each,for introduction of lavage fluid into the uterine cavity. The openings46 c are oriented to direct the spray of lavage fluid away from thefallopian tubes 266, 268. Each supply line 46 a, 46 b terminates in aninflatable cornua balloon 46 d for blocking the fallopian tube ostium270 to limit or prevent leakage of fluid into the fallopian tubes. Thesupply lines 46 a, 46 b are biased, for example, by a nitinol wire, toexpand outward when advanced. Connected to the handle 50 is a inflationsupply line 272, syringe 274, and stopcock 276 for inflating anddeflating the balloons 46 d. Fluid aspiration (FIG. 45) occurs near theinternal cervical os 230 and can be through a lumen located betweensupply lines 46 a, 46 b or through lumen 78 (FIG. 3A).

Referring to FIGS. 46 and 47, a uterine embryo retrieval device 10 dhaving an inner catheter 40 that terminates in an atraumatic,semi-permeable absorbent head 48 a includes a suction recovery line 32but no fluid inlet line. The absorbent head 48 a has a swabbing,sponge-like effect that absorbs blastocysts 20 in the uterine cavity,which are then suctioned through the inner catheter 40 and the suctionrecovery line 32. The device 10 d is steerable so the operator can movethe absorbent head 48 a to different regions of the uterine cavity.Alternatively, the device 10 d does not include a suction recovery lineand the blastocysts 20 are recovered on the absorbent head 40 a.

Referring to FIGS. 48-51, a lavage device 10 e includes an activatableseal in the form of expandable foam 18 a. The foam 18 a is compressedprior to insertion and expands within the cervix to seal the uterinecavity from the external environment, as illustrated in FIG. 51.

Referring to FIG. 52, rather than having the collection bottle 34mounted to the cart 100, as shown in FIG. 15, the collection bottle 34can hang off the device 10 with the suction line 36 running to the cart100.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A process for recovering one or more blastocystsfrom the uterus of a human, comprising: placing a device trans-vaginallyinto the cervical canal; and cyclically delivering fluid through thedevice to the uterus in at least two cycles wherein the first cyclecomprises delivering a first amount of fluid to form a first puddleencompassing the one or more blastocysts and applying a vacuum to theuterus to aspirate fluid and entrained blastocysts within the firstpuddle from the uterus; and the second cycle comprises delivering alarger amount of fluid into the uterus to form a second, larger puddleand applying a vacuum to the uterus to aspirate fluid from the uterus,wherein a fluid delivery port for delivering fluid into the uterus and asuction port for aspirating fluid and entrained blastocysts from theuterus are provided such that in use fluid is deliverable from the fluiddelivery port to travel through the suction port to the uterus.
 2. Theprocess of claim 1, wherein the fluid delivery port is non-circular inshape to provide directional control of fluid spray.
 3. The process ofclaim 1, further comprising a controller programmed to automaticallycyclically deliver lavage liquid to the uterus and apply vacuum to thedevice from a vacuum source remote from the device.
 4. The process ofclaim 3, wherein the controller includes a pump for delivering thelavage liquid and a pump for applying the vacuum.
 5. The process ofclaim 4, wherein the controller includes electro-mechanical means forcontrolling the delivery of lavage fluid and the application of vacuum.6. The process of claim 3, wherein the controller is programmed tocyclically deliver varying amounts of lavage liquid to the uterus inthree or more cycles with the amount of fluid delivered increasing ineach subsequent cycle.